(1) We analyzed our 4-year case-control study of severe malaria in Pursat, Cambodia, and found that increasing age (but not hemoglobin E) confers protection against severe disease. (2) We analyzed our 4-year case series of vivax malaria in Pursat, Cambodia, and found that common red blood cell polymorphisms do not suppress parasitemias or reduce vivax malaria risk. (3) We measured parasite recrudescence rates following dihydroartemisinin-piperaquine treatment in patients with falciparum malaria in Pursat, Preah Vihear and Ratanakiri provinces and found that the prevalence of ACT failure is 45, 17, and 3%, respectively, and that the parasites that failed treatment had developed both artemisinin and piperaquine resistance. (4) In a genome-wide association study of in-vitro piperaquine response, we identified a nonsynonymous single-nucleotide polymorphism that predicts a 10-fold increase in risk of dihydroartemisinin-piperaquine failure, and that can now be used as a genetic marker of piperaquine resistance in Cambodia and perhaps elsewhere in Southeast Asia. (5) We conducted a clinical trial of artesunate + mefloquine in the treatment of dihydroartemisinin-piperaquine resistant parasite infections and found this ACT to be 100% effective. This finding supports further clinical trials to investigate whether the triple ACT dihydroartemisinin-piperaquine + mefloquine is safe, tolerated, and effective in the treatment of falciparum malaria in Cambodia, and suggests that artesunate + mefloquine can be used as a stopgap measure until new antimalarial compounds progress through clinical trials. (6) Through whole-genome sequence analysis, we identified subpopulations of artemisinin-resistant P. falciparum parasites in Pursat and Preah Vihear, Cambodia, and discovered four mutations that constitute a genetic background on which K13 mutations arise and confer artemisinin resistance. This genetic background can now be used in surveillance studies as a pre-marker for areas at risk of developing artemisinin resistance in the future. (7) Using genetically-edited parasites, we confirmed that K13 mutations cause artemisinin resistance in vitro. (8) We found that artemisinin-resistant parasites from Cambodia infect diverse anopheline vectors of Southeast Asia and Africa, suggesting mosquito-parasite incompatibility present no strong barrier to the global spread of these parasites. (9) We produced the largest collection of recombinant parasite invasion ligands to date, and showed that they are immunoreactive in seroepidemiological studies in Cambodia. The role of these proteins in eliciting naturally-acquired and vaccine-induced protective immune responses can now be investigated.